Ribwort Plantain – Plantaginis lanceolatae folium (Plantago lanceolata L.)
|Latin name of the genus:||Plantaginis lanceolatae folium|
|Latin name of herbal substance:||Plantago lanceolata l.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Ribwort plantain|
Latin name of the genus: Plantaginis lanceolatae folium
Botanical name of plant: Plantago lanceolata L.
English common name of herbal substance: Ribwort Plantain
2.2.Information on traditional/current indications and specified substances/preparations . 13
2.3.Specified strength/posology/route of administration/duration of use for relevant
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Definitions of the herbal substance
European Pharmacopoeia 6th ed. 2010 (6.7): ‘Plantaginis lanceolatae folium – Ribwort plantain’ ‘Whole or fragmented, dried leaf and scape of Plantago lanceolata L.s.l.’
Deutsches Arzneibuch 2005 (DAB 2005 – German Pharmacopoeia): ‘Spitzwegerichkraut’ ‘The whole or cut, dried herb of Plantago lanceolata L.’
The monograph for ribwort plantain herb, which had appeared in the German Pharmacopoeia, has been replaced by the monograph for ribwort plantain leaf, published in the European Pharmacopoeia. Ribwort plantain herb mainly consists of leaves, therefore the title ‘Plantaginis lanceolata, folium’ has been chosen.
ESCOP Monographs 2nd ed. 2003: ‘Plantaginis lanceolatae folium/herba – Ribwort plantain leaf/herb’
‘Ribwort plantain leaf consists of the dried leaves of Plantago lanceolata L.’
‘Ribwort plantain herb consists of the dried flowering aerial parts of Plantago lanceolata L.’
Österreichisches Arzneibuch (ÖAB 90 – Austrian Pharmacopoeia 1991): ‘Folium Plantaginis, Spitzwegerichblatt’
‘The dried leaf of Plantago lanceolata L.’
Pharmacopoea Helvetica VII (Swiss Pharmacopoeia): ‘Plantaginis folium’
‘Ribwort plantain leaf consists of the dried leaf of Plantago lanceolata L. sensu latiore’
Plantago lanceolata L. is a species of the genus Plantago in the Plantaginaceae botanical family, known by the following common names:
German: Spitzwegerich, Heilwegerich, Wundwegerich (Wichtl 2004);
English: Ribwort plantain, Ribwort, English plantain,
French: Feuilles (herbe) de plantain (Blaschek et al. 2008);
Italian: Piantaggine (Blaschek et al. 2008).
Plantago lanceolata L. is a common perennial weed of arable fields and grassland (Bond et al. 2007), abundant throughout Europe, North- and Central Asia (Wichtl 2002). It is native in grassy places on neutral or basic soils (Bond et al. 2007). The herb is a common roadside plant (Bond et al. 2007) and is found in lawns (Sagar and Harper 1964). It is relatively drought resistant and is able to grow on dry sites such as embankments and chalk grassland (Bond et al. 2007).
Plantago lanceolata L. has a slight, unspecific odour similar to hay and a slightly salty and faintly bitter taste (Blaschek et al. 2008). The plant is a
Plantago lanceolata L. generally flowers from May to August (Bond et al. 2007) but flowering may begin in April and continue till the first frost (Sagar and Harper 1964). Flowers are wind pollinated although insects visit to collect pollen (Warwick and Briggs 1979).
Adulteration and confusion
Confusion with leaves of Plantago major, Plantago media or Digitalis lanata is possible (Blaschek et al.
Principal components of the herbal substance
The herbal substance contains about
The herbal substance is commonly dried at temperatures of
Other drug constituents include
Flavonoids include apigenin and luteolin as well as their derivatives with the main compounds apigenin-
The herbal substance also contains 6.5% tannins, phenolic carboxylic acids including p-
and antimicrobial saponin are also present, as well as volatile oil. Inorganic constituents include 1% silicilic acid and mineral salts with a high proportion of zinc and potassium (Wichtl 2004).
A rather broad spectrum of different herbal preparations has been marketed so far. According to the overviews of the market in the Member States of the European Union, there were herbal preparations with a
Herbal preparations which have been reported to be marketed so far under
Herbal preparations which have been reported to be traditionally used:
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
In many countries, Plantaginis lanceolatae folium is used in combinations with other herbal substances/herbal preparations usually administered for the treatment of complaints associated with colds, or for the treatment of inflammations of the mouth and throat. The main combination substances are Thymi herba, Foeniculi fructus, Salviae folium, Primulae radix, Sambuci nigrae flos, Tiliae flos, Liquiritiae radix, Matricariae flos, Menthae piperitae herba, Althaeae radix, Rubi fruticosi folium, Lupuli flos, Serpylli herba, Salviae officinalis herba, Polygonii avicularis herba, Urticae herba, Farfarae folium, Verbasci flos, Cynosbati fructus sine semine, Gentianae radix, Pini montanae turioni, Menthae piperitae aetheroleum, Foeniculi aetheroleum and Anisi aetheroleum. This monograph refers exclusively to Plantaginis lanceolatae folium.
1.2. Information about products on the market in the Member States
According to the information provided by the National Competent Authorities the following herbal substances and herbal preparations have been on the European market. The data are derived from the overview of marketed products in Europe.
In Austria, a syrup is prepared from Plantago lanceolata leaf according to the instructions of ÖAB 2009 is commonly used. It is administered for the treatment of catarrhs of the upper airways at a dosage of 1 tablespoon
As a traditional use of at least 30 years is given, this preparation was included in the monograph.
In Germany, for herbal preparations of Plantago lanceolata both a traditional and a
ethanol 20% m/m
8)liquid extract (1:1); extraction solvent: ethanol 24.6% V/V
9, 10, 11)
expressed juice from fresh Plantaginis lanceolatae herba
15)liquid extract (1:1); extraction solvent: ethanol 40% V/V
19)Plantaginis lanceolatae herba, cut
Since when are the preparations on the market
Traditional use: In Poland, various herbal preparations containing Plantago lanceolata with a traditional indication are on the market. None of them, however, fulfil the requirement of a medicinal use for at least 30 years and thus inclusion in the monograph was not possible.
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
1.3. Search and assessment methodology
A literature research on Plantago lanceolata was performed by DIMDI and LIDOS in August 2008. The key words were “Plantago lanceolata” and “Spitzwegerich”. The literature research was updated in April 2010. Additional literature was provided by the EMA.
The regulatory status of Plantago lanceolata preparations in the EU Member States was requested on 14 October 2008. In Germany, these data were obtained by means of AMIS.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
2.2. Information on traditional/current indications and specified substances/preparations
The following traditional uses and posologies have been recorded for Plantago lanceolata:
Monograph Plantaginis lanceolatae herba of the German Commission E (1985)
Indications for the internal administration are catarrhs of the respiratory tract and inflammation of oral and pharyngeal mucosa. Externally applied it is used for inflammation of the skin.
The mean daily dosage is
ESCOP Monograph Plantaginis lanceolatae folium/herba (2003)
Indications for the oral administration are catarrhs of the respiratory tract and temporary, mild inflammations of the oral and pharyngeal mucosa.
The average daily dose in adults and elderly is
German standard registration “Spitzwegerichkraut” (1996)
For a tea from the herb of Plantago lanceolata indications are the same as listed in the monograph Plantaginis lanceolatae herba of the German Commission E.
The dosage for the tea is
For rinsing and gargling, as well as for compresses, a cold macerate is prepared
Based on literature and on the results of a survey in physicians according to Madaus (1976), Plantago lanceolata is administered in medical practise for the strengthening of mucosa and skin. It is given with very high success in diseases of the respiratory tract with severe mucous production and is also administered in diseases of the urinary bladder and gastrointestinal tract. Furthermore, its use as haemostypic and local application in wounds and ulcers has been described. The usual dosage is 3 g of
the herb for a cold macerate or hot infusion,
Use of Plantago lanceolata in folk medicine:
The use of Plantago lanceolata for the treatment of wounds in folk medicine extensively described by Brøndegaard (1963). Loew et al. (1997) mention Plantago lanceolata as mucilage drug which can be used against dry cough caused by pharyngitis. According to Hoppe (1975) Plantago lanceolata is used as a mucilage drug and mild expectorans. In folk medicine it is administered in catarrhs of the upper respiratory tract. Due to its positive
There are further reports of the use of Plantago lanceolata in folk medicine:
In Turkey, fresh Plantago lanceolata leaves are applied to abscess to promote suppuration (Sezik et al. 2001).
In Guatemala, the herbal substance is administered in conjunctivitis/eye irritation and for the treatment of wounds, ulcers, bruises and sores (Cáceres et al. 1987).
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
See 1.2. and 2.2.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Plantago lanceolata has traditionally been regarded as a mucilage drug. The mucilage polysaccharides, mainly arabinose and galactose (Bräutigam and Franz 1985), are not resorbed and cover the mucosa with a protective layer against local irritations (Franz 1989,
Beyond this, pharmacological effects are attributed to the following constituents of Plantago lanceolata (Blaschek et al. 2008, Marchesan et al. 1998a):
Iridoid glycosides: mainly aucubin and catalpol
Flavonoids: mainly apigenin and luteolin
Phenylethanoids: acteoside, plantamajoside
Phenol carboxylic acids
In vitro and in vivo pharmacological investigations have been performed with the total extract and with isolated agents from the total extract. When not specified, the plant part is not known.
Other effects reported for isolated agents of Plantago lanceolata include anthelmintic and cytotoxic properties.
(500 μg/pellet vs. 50 μg) the
The effects of extracts from Plantago lanceolata (leaves, flowers, roots) on mediators of inflammation have been investigated in vitro in murine macrophages (Vigo et al. 2005). They inhibited the production of nitric oxide in this cell line and significant scavenging of nitric oxide radicals. Pre- treatment with these extracts did not affect
Herold et al. (2003a) investigated in vitro if a standardised hydroalcoholic extract from Plantago lanceolata leaves can suppress in
In vivo studies with dried frozen extracts from Plantago lanceolata leaves showed that in
In connection with the
Herold et al. (2003b) investigated the possible mode of action of the antioxidant potential of a hydroalcoholic extract from Plantago lanceolata leaves standardised to mucilaginous substances. The antioxidant property was measured using a colorimetric assay and the free radical scavenging potential by means of activated human polymorphonuclear neutrophils (PMNs). For the extract, a minor antioxidant status and the capacity of scavenging free radicals released by activated PMNs were observed.
The antioxidant activity of a methanol extract from the aerial parts of Plantago lanceolata was studied by Gálvez et al. (2005) using the DPPH scavenging test and lipid peroxidation inhibition assay, in which this extract was found to be the most active as compared to methanol extracts from other Plantago species.
Antioxidant effects have also been observed for single compounds such as acteoside (Ji et al. 1993, Pan and Hori 1996, Wang et al. 1996; Li et al. 1996, Hausmann et al. 2007), various polysaccharides (Kardosová and Machová, 2006) and flavonoids (Catapano 1997, van Acker et al. 1996, Fraga et al. 1987).
In vitro investigations with pressed juice and aqueous extracts of Plantago lanceolata showed antibacterial effects against Staphylococcus aureus, Streptococcus
Staphylococcus aureus (Cáceres et al. 1987).
It is assumed that aucubigenin is responsible for the in vitro antibacterial effects of Plantago lanceolata (Elich 1962, Hänsel 1966, Elich 1966, Elich 1961), as aqueous extracts with inactivated
The antibacterial and antifungal activity of an ethanolic extract from Plantago lanceolata were also investigated by Orhan et al. (2002) by agar diffusion and microdilution methods using E. coli, Proteus mirabilis, Enterococcus faecalis, Acinetobacter baumanni, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumonia, Candida albicans, Candida kruzei and Candida parapsilosis. Antibacterial or antifungal effects were not observed for Plantago lanceolata.
Regarding single compounds of Plantago lanceolata acteoside exerted only weak antibacterial effects on E. coli (Molnár et al. 1989). The isolated compounds aucubin and saponin and extract of the Plantago lanceolata leaves showed antibiotic effect. Extract of Plantago lanceolata leaves and aucubin had antibiotic effects on Streptococcus aureus 209 P and Micrococcus flavus, whereas the antibiotic activity of the saponin compound was limited to Micrococcus flavus (Tarle et al. 1981).
An ethanolic extract from Plantago lanceolata herba (DER 1:1) (Fleer et al. 1997) and an ethanolic (20%) soft extract of Plantago lanceolata (Fleer and Verspohl 2007) inhibited the ileum contractions caused by acetylcholine, histamine, potassium and barium ions and barium induced tracheal contractions in
Spasmolytic activity has been attributed to the iridoids aucubin and catalpol (Urbina et al. 1994) and acteoside (Schapoval et al. 1998). Fleer and Verspohl (2007) observed antispasmodic effects for luteolin, acteoside, plantamajoside and catalpol peracetate.
Abdin (2006) observed positive effects of tea from Plantago lanceolata leaves in one patient with AIDS- related complex and suggests that further research might explore a possible role for Plantago lanceolata in the treatment of
Antiviral effects on Aujezky virus (Molnár et al. 1989) and
virus (Chang 1997). Catalpol showed to be active against hepatitis B virus antigens (HBsAg) in HBsAg positive serum (Mehrotra et al. 1990). For caffeic acid and chlorogenic acid (Chattopadhyay et al. 2008, Zanon et al. 1999, Chiang et al. 2002) as well as saponins and tanning agents (Büechi 1998, Büechi 1996) antiviral activity was shown, too.
Protective effects have been attributed to Plantago lanceolata. It has been reported that pressed juice from Plantago lanceolata had antitoxic effects on the damaging effects of
Antitumor activity was observed in vitro for acteoside and seems to be due at least in part to inhibition of protein kinase C (Herbert and Maffrand 1991). Flavonoids were shown to inhibit tumour promoter- induced histamine release in a
The hepatoprotective activity of an ethanolic extract from Plantago lanceolata leaves was investigated using
Hepatoprotective effects were observed for aucubin (Chang et al. 1984a, Chang et al. 1984b, Chang and Yamaura 1993), acteoside (Xiong et al. 1998, Yamahara et al. 1990, Pan and Hori 1996) and catalpol (Garg et al. 1994).
In vitro and in vivo, an aqueous extract from Plantago lanceolata leaves caused a significant increase of antibody formation and release of angiogenesis factor in lymphocytes of man and mouse (Strzelecka et al. 1995). An aqueous decoction of Plantago lanceolata leaves stimulated the production of interferon in mice (Plachcinska et al. 1984).
Immunomodulatory effects were shown for several compounds of Plantago lanceolata: polysaccharides derived from Plantago lanceolata leaves (Bräutigam 1985, Ebringerová et al. 2003), aucubin and chlorogenic acid (Chiang et al. 2003), catalpol (Wegener and Kraft 1999, Garg et al. 1994) and acteoside (Marchesan et al. 1998). For acteoside, immunosuppressive effects were reported by Sasaki et al. (1989).
Aqueous extracts from Plantago lanceolata are said to promote epithelising and scaring of wounds and to reduce hyperemia (Blaschek 2008, Heil and Kammerer 1993). According to Pahlow (1984) fresh ground Plantago lanceolata leaves are effective in inflammation or irritation of the skin caused by insect stings (Brøndegaard 1963).
Aqueous extracts increased coagulation in vitro and in vivo (Blaschek et al. 2008, Keeser 1939). An extract (1:1) stimulated the coagulation of blood in rabbits, a 1:10 infus. reduced coagulation time in dilutions of 1:5 to 1:40. Following injection into the femoral vein (v. femoralis) of the cat, an acceleration of coagulation was observed.
Ethanolic and aqueous extracts from Plantago lanceolata leaves displayed significant anthelmintic activity against pinworms in mice (Kozan et al. 2006).
Cytotoxic effects for single compounds of Plantago lanceolata have been observed by Gàlvez et al. (2003). Methanolic extracts from Plantago lanceolata leaves showed growth inhibitory and cytotoxic effects in vitro on breast adenocarcinoma and melanoma tumoral cell lines, which might be due to the cytotoxic activity of the flavone
In an in vitro investigation in rat hepatoma cells, an increased breaking of DNA chains as well as increased proapoptoctic effects occurred following luteolin concentrations > 100 μM (Steffan 2005). In contrast to this observation for flavonoids, anticancerogenic effects have been described after in vitro concentrations of
A saponin substance (not identified) isolated from the leaves of Plantago lanceolata showed haemolytic activity (Tarle et al. 1981).
Effects on mucociliary transport
Mucociliary transport was investigated by viscosimetry using a ciliated epithelium preparation of a frog. A 4.6% extract from Plantago lanceolata did not increase mucociliary activity
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
There is a report on the pharmacokinetics of aucubin in rats (Suh et al. 1991). Linear kinetics were observed following the intravenous administration of
In rabbits, aucubigenin accumulates in urine when fed with the drug (Freerksen 1950).
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
No acute or chronic toxicity tests were performed on any of the herbal preparations of Plantago lanceolata included in the monograph.
Aucubin can cause gastroenteritis and central palsy following oral administration (Blaschek et al. 2008).
Following maximum aucubin doses of 900 mg/kg bodyweight, no deaths occurred in mice (Chang 1985).
Maximum aucubin doses of 800 mg/kg bodyweight 4 times a week did not cause significant changes of liver transaminases, alkaline phosphatase, triglycerides, glucose, blood urea nitrogen and total protein. Liver biopsies did not reveal relevant changes (Chang 1985).
Mutagenicity and cancerogenicity
Ruiz et al. (1996) screened several plants for genotoxic activity by means of induction of somatic segregation in Aspergillus nidulans. A fluid extract from Plantago lanceolata (40% ethanol) showed no statistically significant increase in the frequency of segregant sectors per colony and thus no genotoxic effects.
Cytotoxic effects of a methanol extract from Plantago lanceolata were observed by Gàlvez et al. (2003); haemolytic activity was described by Tarle et al. (1981) for a saponin substance isolated from the leaves of Plantago lanceolata. In an in vitro investigation in rat hepatoma cells, an increased breaking of DNA chains as well as increased proapoptoctic effects occurred following luteolin concentrations > 100 μM (Steffan 2005) (see section 3.1).
In an investigation with 1000 dogs, Plantago lanceolata caused atopic dermatitis in > 15% of the animals (Mueller et al. 2000).
3.4. Overall conclusions on
A variety of pharmacological effects have been reported for Plantago lanceolata extracts and other preparations and for its compounds. Most of the investigations are quite old, while more recent investigations have mainly been performed with isolated compounds of the plant. As so far, only the concentration of the iridoid glycosides aucubin and catapol has been determined (Long et al. 1995, Jurisic et al. 2004), it is not possible to assess to which extent the different reported effects of Plantago lanceolata extracts could be attributed to these single compounds.
The pharmacological effects described in literature, however, support both the oral and oromucosal traditional use of herbal preparations of Plantago lanceolata as a demulcent for the symptomatic treatment of irritations of oral and pharyngeal mucosa with associated dry cough.
So far, pharmacokinetic investigations have only been performed with aucubin and not with the total extract.
Data on pharmacokinetics in man are not available. Due to the low bioavailability of aucubin, it is unclear to which extent the pharmacological effects observed in vitro and in vivo experiments contribute to the efficacy of the total extract and are of clinical relevance.
There are no data available on the toxicity tests with preparations from Plantago lanceolata. No reproduction or developmental toxicity tests have been performed. An administration of Plantago lanceolata thus cannot be recommended during pregnancy and lactation. The investigation of genotoxiciy by Schimmer et al. (1994) is assessed as insufficient, as the Ames test performed included only 2 stems of Salmonella typhimurium instead of 5 as required.
Regarding the cytotoxic effects observed for luteolin, it is supposed that there is no risk in man, as the bioavailability of flavonoids following oral administration is only poor and only low concentrations of the mutagenic active flavonoids can be found (Teuscher et al. 2004). The luteolin concentration used in the in vitro experiments thus is not reached under physiological conditions.
With regard to the potential toxicity of aucubin, its minimum lethal dose in mouse of > 0.9 g have to be taken into account so that aucubin is regarded as a low toxic substance (Chang et al. 1983). Due to the low content of aucubin in Plantago lanceolata, the safety of the herbal substance does not seem to be affected when used in clinical practice and intoxications with Plantago lanceolata have not been observed.
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No human data available.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No human data available.
4.2. Clinical Efficacy
4.2.1. Dose response studies
Dose response studies have not been performed.
4.2.2. Clinical studies (case studies and clinical trials)
There is only one
A total of 593 patients (mean age 42 years, range
As controlled clinical trials with extracts from Plantago lanceolata have not been performed a well- established use cannot be accepted. The results of the
4.2.3. Clinical studies in special populations (e.g. elderly and children)
The results of the
A dosage recommendation for children is given by the Kooperation Phytopharmaka (1998) and was calculated on basis of the dosage for adults which correspond to the dosage as defined in the monograph of the Commission E. The mean daily dose of the herbal substance for children is as follows (internal administration):
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The mean daily dose for children based on the results obtained by a survey in 31 doctors are as follows (internal administration):
In children only data for the oral administration are available.
4.3. Overall conclusions on clinical pharmacology and efficacy
Controlled clinical studies, which might support a
The traditional use, however, is well documented. Apart from the results of one
In literature there is also evidence of a traditional use of Plantago lanceolata for the external treatment of irritations of the skin, but so far only one medicinal product has been registered in Poland. This preparation, however, does not fulfil the requirement of a traditional use for at least 30 years.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
Nevertheless, for Plantago lanceolata a high risk of sensitisation is reported by Blaschek et al. (2008). About 30% of patients with pollinosis are allergic to pollen from Plantago lanceolata (Wüthrich et al. 1977, Horak and Jäger 1980).
One report of an allergic adverse event was received by the German Health Authority. Following the intake of a medicinal product containing Plantago lanceolata, a
5.2. Patient exposure
Apart from its medicinal use, Plantago lanceolata is also available on the
5.3. Adverse events and serious adverse events and deaths
See chapter 5.1.
5.4. Laboratory findings
None reported for Plantago lanceolata.
5.5. Safety in special populations and situations
See chapter 5.1.
5.6. Overall conclusions on clinical safety
The oral and oromucosal administration of Plantago lanceolata is generally recognised as safe. Due to the lack of adequate data, however, its use cannot be recommended during pregnancy and lactation. In children younger than 3 years, Plantago lanceolata and preparations thereof should not be used, as there are only limited data on the oral use in children. In addition, in relation to children of this age, a doctor should be consulted to make a diagnosis before the start of treatment, otherwise there is a risk that severe infectious diseases of the upper respiratory tract, such as laryngitis, are misinterpreted as a common cold. Data on a safe oromucosal application in children and adolescents are missing, too.
The cutaneous use of Plantago lanceolata is not recommended at all, since data on the topical application are completely missing.
6. Overall conclusions
The use of Plantago lanceolata as demulcent in the symptomatic treatment of oral and pharyngeal irritations and associated dry cough fulfils the requirement of at least 30 years of medicinal use (including at least 15 years with the European Union) according to the traditional use provisions of Directive 2001/83/EC as amended.
There is sufficient evidence in literature for the traditional oral and oromucosal use in the above mentioned indication. Although various pharmacological effects have been described for the total extract of Plantago lanceolata and constituents thereof, these effects have never been verified in controlled clinical studies. A
The oral administration has been investigated in a
The oromucosal administration is recommended only for elderly and adults, as data in children and adolescents are completely missing.
Due to the lack of data of its safe administration during pregnancy and lactation, this patient group should also be excluded from administration.